Epigenetic Control of Developmental Processes and Genome Function in Mammals
Our lab focuses on the molecular events governing pre- and post-natal mammalian development. Our research is focused on two areas; investigating the developmental role of imprinted genes and the epigenetic mechanism(s) controlling their parental-origin specific expression and the epigenetic control of genome function during development in a wider context.
Genomic imprinting and parental-origin effects
Genomic imprinting is a remarkable normal process that causes some genes to be expressed solely from maternally inherited chromosomes and others from paternally inherited chromosomes. This means that the egg and sperm contribute unequal functions to the developing conceptus through the parental-origin specific expression of imprinted genes. In mouse and man, disorders can arise when the dosage of imprinted genes is altered through imbalances in the parental-origin of particular chromosomes, by mutations in the single active allele or by mutations affecting the imprint process. Over the years we and others have contributed to understanding aspects of genomic imprinting including the epigenetic mechanisms that programme functional differences between the two parental chromosomes and generate a heritable memory of parental origin. More recently, our work has focused on the processes required to maintain this memory during the period of preimplantation epigenetic reprogramming when most of the genome erases then re-establishes new epigenetic states. In addition, we have explored the function of imprinted genes in development and disease and the evolution of imprinting and its epigenetic control. Much of our work has focused on the Dlk1-Dio3 imprinted domain on mouse chromosome 12 which contains paternally expressed protein coding genes and multiple non-coding RNAs expressed specifically from the maternally inherited chromosome.
Epigenetic control of genome function in a wider context
More recently we have been using genomic imprinting as a paradigm for understanding aspects of genome function and its epigenetic control in a wider context. This has taken us on several scientific journeys including studying of the importance of dosage control in in vivo stem cell niches, exploring the environmental modulation of epigenetics states and a consideration of the mechanisms that might contribute to non-DNA sequence based inheritance in mammals. We have recently generated and integrated high quality genomic, epigenomic and transcriptomic datasets from purified populations of ex vivo cells allowing us to explore the relationship between particular genomic features including the repeat genome, epigenetic state and phenotype using inbred strains of mice.
Current research themes
Our current programme is divided into three integrated research themes:
1. Stem cells and the epigenetic programme in vitro and in vivo
2. Functional genomics and epigenomics
3. Development, environment and disease
The lab currently integrates both ‘wet’ and ‘dry’ research with bioinformatics and in silico genomics activities taking place alongside molecular genetics laboratory research, high-throughput genomics, stem cell and tissue culture approaches and the use of mouse (and currently zebrafish) genetic and developmental models.
Selected recent publications
- Quantitative comparison of DNA methylation assays for biomarker development and clinical applications. BLUEPRINT consortium. Nature Biotechnol. 2016 Jul;34(7):726-37. doi: 10.1038/nbt.3605
- Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity. Dalgaard K, Landgraf K, Heyne S, Lempradl A, Longinotto J, Gossens K, Ruf M, Orthofer M, Strogantsev R, Selvaraj M, Lu TT, Casas E, Teperino R, Surani MA, Zvetkova I, Rimmington D, Tung YC, Lam B, Larder R, Yeo GS, O'Rahilly S, Vavouri T, Whitelaw E, Penninger JM, Jenuwein T, Cheung CL, Ferguson-Smith AC, Coll AP, Körner A, Pospisilik JA. Cell. 2016 Jan 28;164(3):353-64. doi: 10.1016/j.cell.2015.12.025
- Differential genomic imprinting regulates paracrine and autocrine roles of IGF2 in mouse adult neurogenesis. Ferrón SR, Radford EJ, Domingo-Muelas A, Kleine I, Ramme A, Gray D, Sandovici I, Constancia M, Ward A, Menheniott TR, Ferguson-Smith AC. Nature Commun. 2015 Sep 15;6:8265. doi: 10.1038/ncomms9265
- A trans-homologue interaction between reciprocally imprinted miR-127 and Rtl1 regulates placenta development. Ito M, Sferruzzi-Perri AN, Edwards CA, Adalsteinsson BT, Allen SE, Loo TH, Kitazawa M, Kaneko-Ishino T, Ishino F, Stewart CL, Ferguson-Smith AC. Development. 2015 Jul 15;142(14):2425-30. doi: 10.1242/dev.121996
- Allele-specific binding of ZFP57 in the epigenetic regulation of imprinted and non-imprinted monoallelic expression. Strogantsev R, Krueger F, Yamazawa K, Shi H, Gould P, Goldman-Roberts M, McEwen K, Sun B, Pedersen R, Ferguson-Smith AC. Genome Biol. 2015 May 30;16:112. doi: 10.1186/s13059-015-0672-7
- In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism. Radford E J, Ito M, Shi H, Corish J A, Yamazawa K, Isganaitis E, Seisenberger S, Hore TA, Reik W, Erkek S, Peters A H, Patti ME, Ferguson-Smith AC. Science. 345(6198): 1255903 (2014)
Page updated 13 September 2016